A Review of Androgen‐Progestin Regimens for Male Contraception

It has been 40 years since the administration of steroids to women to prevent pregnancy was approved in many countries, and finally the development of reversible hormonal contraceptives for men seems to be within reach. Surveys performed in recent years suggest that men are willing to share the responsibility of family planning (Glasier et al, 2000, Martin et al, 2000). Worldwide, about 30% of the couples that use contraception use a male method in spite of the evident shortcomings of currently available contraceptives for men. In 1994 at the International Conference on Population and Development, active involvement of men in family planning was given a high priority in the women agenda. Thanks to public agencies like the World Health Organization (WHO) and the Contraceptive Research and Development Program, the validity of the concept of the hormonal approach to male contraception were proven in large-scale clinical trials. In these studies it was shown that hormones can provide contraceptive protection that promises to be as effective in men as in women (WHO, 1990, 1996). Achievement of azoospermia has been suggested to be the gold standard for this method in order to confer optimal contraceptive protection (WHO, 1990, 1996). Azoospermia achieved with weekly injections of 200 mg of testosterone enanthate (TE) provided a Pearl index (pregnancy per 100 person-years) rating of 0.8 (95% confidence interval [CI] = 0.02–4.5]; WHO, 1990). However, various degrees of severe sperm suppression also have been shown to provide acceptable contraceptive protection. When sperm count is suppressed to azoospermia or severe oligozoospermia (sperm count from 0 to 1 × 106/mL), contraceptive protection is provided to a Pearl index rating of 1.4 per 100 couple-years (95% CI = 0.4–3.7; WHO, 1996). Therefore, induction of azoospermia or sperm suppression to <1 million/mL can be considered an acceptable contraceptive goal. Studies performed in the last decade have shown that testosterone (T) administration alone can provide almost universal azoospermia in diverse Asian populations, with minimal side effects (WHO, 1990, 1996). Therefore, phase II and III clinical trials are already being planned with androgen regimens in the Asian population. The encouraging preliminary results of these studies offer some promise that an androgen-alone contraceptive may be on the market in those countries within the next few years (Zhang et al, 1999). Testosterone-alone regimens are not as effective in the Caucasian population as they are in the Asian population, but small-scale clinical trials performed over the last few years have suggested that if a progestin is added to the androgen, profound suppression of sperm production can be achieved in Caucasian men (Meriggiola and Bremner, 1997). In spite of the fact that all of these studies have shown that hormonal contraception for men is feasible and effective, the lack of involvement of drug companies has prevented the transit of these concepts from small pilot trials to large-scale studies aimed at the development of suitable products for the market. In 1997, a group of leading researchers promulgated a manifesto on male contraception. The aim of this manifesto was to sensitize drug companies, politicians, and research foundations “to commit themselves to the development of male contraception for the sake of future generations” (Nieschlag and Behre, 1998). This appeal was finally received and in November 2002 when 2 major pharmaceutical companies committed themselves to the development of a hormonal contraception for men (Schering AG, 2002). Large-scale clinical trials are now being planned with various combinations of progestins and androgens to confirm and extend the preliminary results obtained in small pilot studies and to eventually test the contraceptive effectiveness of these combinations. Advantages of this hormonal combination include the vast experience of years of clinical use of both classes of compounds and their relatively low cost. The purpose of this article is to review the literature on androgen-progestin combinations, to understand lessons learned from these trials, and to determine how these results can be applied to the design of large multicenter clinical trials with the ultimate goal of developing an optimal hormonal male contraceptive. This review includes all studies reporting the outcome of androgen-progestin regimens, in terms of sperm suppression, published in the peer-reviewed literature between 1960 and September 2002. For this review, the database MEDLINE was searched. English-only publications were included in the search, and subsequent bibliographies were cross-referenced. Where more than 1 publication reported the same study, the data were analyzed only once. For a detailed breakdown of the various studies, please refer to the tables. Because of the apparent ethnic differences in responsiveness to steroids, results from clinical trials of potential hormonal contraceptive regimens have been analyzed and reported separately in the Asian and Caucasian populations. Healthy subjects of all ethnic groups, within an age range of 21–50 years and with normal seminal parameters, were included in the studies. Only studies in which hormone administration lasted longer than 12 weeks were included in the analyses. Maximal suppression of sperm count (rate of azoospermia) was considered for all studies. In most of the papers it coincided with the end of the study, but in many papers it could not be detected at which time of the study maximal sperm suppression occurred. Only rate of azoospermia is considered for analysis in this paper, since the degree of sperm suppression was not always clearly reported in the results sections of the various studies. Gonadotropin suppression could not be considered in this review, since the different gonadotropin assays and their evolution throughout the years would not allow for a comparison among the studies. The rates of azoospermia observed in each study were plotted according to the regimen, and the mean rate of azoospermia was calculated. The total number of azoospermic men, as well as the total number of treated cases, were also reported in the text of the figures. These numbers were used for the comparison between different regimens by evaluating the Yates corrected chisquared test and the odds ratio (OR) together with the 95% CI. Statistical evaluations were performed by the SPSS/PC+ statistical package version 5.0 (Dixon et al, 1990; Norusis, 1992). The mechanism(s) by which gonadal steroids inhibit male fertility is the suppression of sperm production achieved through inhibition of gonadotropin secretion. The various progestins have different antigonadotropic potency: 19-nortestosterone derivatives have a stronger suppressive effect on gonadotropins compared with the progesterone-derived progestins. The mechanism by which progestins suppress gonadotropins is still unclear. Although previous studies attributed the antigonadotropic effect of progestin to their androgenic activity, more recently a possible direct inhibitory effect of these compounds on gonadotropin secretion has been postulated (McEwen et al, 1983; Couzinet et al, 1996). The direct inhibitory effect of progestins on gonadotropins, independent of estrogens and androgens, could also explain the additive and synergistic effects of this compound when combined with other steroids, in this case androgens. Progesterone receptors have been found both at the hypothalamus and pituitary level in rats and nonhuman primates. After exogenous administration of sex hormones such as androgens, progestins, or estrogens, Leydig cells decrease in volume; consequently, serum T production also decreases (Flickinger, 1977a, b). T levels fall below physiological levels both intratesticularly and in the peripheral circulation (Morse et al, 1973; McLachlan et al, 2002). Therefore, administration of androgens or androgen-like substances to re-establish peripheral physiological T levels is mandatory for non—T-alone hormonal contraceptive regimens that act through this mechanism to maintain androgen-dependent physiological functions. As a result of FSH and intratesticular T suppression, studies in both animals and humans have demonstrated that after hormone administration, sperm development stops at the pachytene spermatocyte stage, whereas degeneration of later stage spermatids occurs (Terner and MacLaughlin 1973; Hikim et al, 1995). This mechanism maintains spermatogonia and thus implies the potential reversibility of the contraceptive method. According to the degree of T depletion from the testis, remaining spermatids and spermatocytes may complete their development or slough from the seminiferous epithelium. This means that hormone regimens require some time to be fully effective over the human spermatogenic cycle of about 70 days. The mean time reported to induce azoospermia ranged from 6 to 12 weeks in most clinical trials. After stopping hormone administration, gonadotropin secretion recovers, resulting in full resumption of Leydig cell function and spermatogenesis. The time for spermatogenesis to resume normal levels has among different studies, from a few weeks to as the result of the effect of some steroids, which may in the However, it be that in all studies performed full of spermatogenesis was always achieved in all This to hormonal male contraception an over other currently available of contraception such as The for androgens with progestins to suppress fertility in men is on the additive and synergistic effects that these 2 steroids have on the suppression of gonadotropins, and thus spermatogenesis. studies have demonstrated that when given alone at that are for administration, currently available progestins not induce profound suppression of gonadotropins, and thus in men and 1973; et al, 1973; et al, et al, et al, et al, and and et al, androgens when at not induce a degree of spermatogenic suppression for contraception (WHO, 1990, 1990). high T levels may induce in some and that may have potential effects et al, et al, 1995). The of androgen and progestin can be to maximal gonadotropin suppression at the same induction of serum androgen the of the In to the effects at the are studies that the of a direct inhibitory of the progestins at the number of studies in animals suggest that progestins may spermatogenesis by a direct effect at and of mechanism(s) have been suggested to explain this may the androgen within the by androgen androgen at the level by the effective level of intratesticular androgens et al, 1983; et al, et al, et al, Studies in animals suggest that various in their and It be that the effects have only been reported in and in at high progestin and their to the for contraception in men is unclear. The of the of effects to the contraceptive effects of this is still was at the end of the and in 1960 the and approved use for of a vast of literature has been published on this which is used in the of a of and for contraception in In men, has been used for the of and and in male contraception. the last 40 papers were published studies in which different regimens were to men for suppression of spermatogenesis These regimens of the or of given in combination with different T total of men at 12 weeks of hormone administration subjects achieved azoospermia of these studies were performed in Asian et al, WHO, of azoospermia of androgen-progestin regimens in the Asian and Caucasian populations. rates of azoospermia achieved with each different androgen-progestin in the populations, were according to the progestin that was in combination with testosterone mean of the azoospermic rates in the 2 of studies. ratio of azoospermia was of azoospermia testosterone (T) in a or rate of azoospermia achieved with each different In both the maximal sperm suppression was mean of the azoospermic rates in the 2 of studies. ratio of azoospermia was text and 2 for of azoospermia injections in combination with testosterone testosterone enanthate testosterone T testosterone and 19-nortestosterone or in combination with T or rate of azoospermia achieved with each different mean of the azoospermic rates in the 2 of studies. ratio of azoospermia was T text and for all other hormonal regimens the rates of azoospermia achieved in the Asian population but were than that achieved in the Caucasian population of the Asian subjects achieved whereas only of the Caucasian subjects azoospermic studies have that such as a different of the pituitary or of the to the suppressive effects of steroids could be between the Caucasian and Asian population et al, 1999). is a in the which can result in a different et al, et al, et al, et al, et al, et al, 1998). this different to the suppressive effects of steroids still be in future studies, the mechanism to be In the Caucasian population, the and the were in combination with or T was given in combination with such as or with and et al, and et al, weeks was given in combination with et al, et al, et al, and et al, et al, et al, and et al, testosterone et al, testosterone et al, et al, 19-nortestosterone or T et al, et al, and combinations were effective than in the suppression of spermatogenesis After administration of of of the achieved azoospermia compared with azoospermic of of the men received the of T was in a or et al, et al, et al, et al, et al, regimens included an which the 2 steroids were at by a phase in which were the regimens, profound sperm suppression was achieved by means of the high of and suppression achieved in this phase was more profound than that achieved with the regimens of subjects azoospermic after an phase of hormone administration, whereas only 40 of subjects achieved azoospermia at the end of a T administration However, in all studies the regimens used in the phase to maintain sperm suppression, and spermatogenesis in most of the subjects in all studies. major effects were reported with of these is a with both and and et al, Because of this combination of has been used in in which a profound suppression of androgen is in men or these a decrease of gonadotropin and T levels and a in sperm production was These researchers to test the that could be used for suppression of male papers have been published in which was given at from 200 to to test effectiveness in spermatogenesis and gonadotropins et al, et al, 1973; et al, et al, et al, and et al, and and These studies were also by the results obtained in which suggested that could inhibit fertility through a direct effect at the men received for azoospermia was only achieved in a few men and not In most of the men, sperm suppression was and various degrees of In these trials, a decrease of sperm and normal was these to a direct effect of at to a of fertility potential of these is unclear. However, major side effects of this included a decrease of both and that was severe in many cases, were to an for In and to with T in order to side effects to androgen 1 and 2 over a of to male animals and of were years the same results were reported after administration of of in combination with of to 6 men and of 6 men and 1 a sperm count <1 million/mL after weeks of In spite of these preliminary this hormonal combination not for 2 these data in men were published in a peer-reviewed and it to an androgen with an This was years The for this hormonal combination was on the combination of and of the may suppress gonadotropins of as well as act at the and the effect of or exogenous intratesticular T on sperm development as the result of The lack of suppressive effect of on sex hormone levels could to the of T which is different than other progestins like which is to decrease levels (Meriggiola et al, studies have been published (Meriggiola et al, 1997, in which was given at of and in combination with 100 or 200 or with testosterone to subjects subjects and in subjects the sperm count million/mL after weeks of hormone administration When the same of was with an or (TE) androgen, the in which T was to be effective than that in which injections were of subjects achieved azoospermia with the combination of subjects in the gonadotropin levels between the 2 regimens, it is evident that gonadotropin suppression was achieved with the combination Although the studies included a small number of it would that the profound gonadotropin suppression achieved with T may be to the serum T levels achieved after which may not be to maintain and sperm suppression (Meriggiola et al, 1997). major side effects were detected with this of function or were with the of a decrease of in the group that received the of was a decrease of cell in all groups, which to be on the of and was to clinical trials may be to test the and of low of with T in of men. of azoospermia administration of testosterone enanthate (TE) injections or testosterone rate of azoospermia achieved with each different mean of the azoospermic rate in the 2 of studies. ratio of azoospermia was testosterone (T) text and for serum FSH and levels after of weekly injections of 100 mg or of throughout the study text and for on studies and clinical studies in progestins are to be in terms of gonadotropin suppression et al, 1996). this of compounds are and the active of this The progestins of this are to be of gonadotropin and when to men these compounds a profound suppression of sperm production However, a decrease of and was also to the suppression of T production to gonadotropin suppression et al, Therefore, like other progestins available thus not be alone for male contraception their androgenic is not to maintain androgen-dependent physiological like or et al, to their or to androgen administration of these progestins in a high rate of et al, et al, 1997). These progestins have been in combination with different androgens. this group of and enanthate and were the most used progestins in clinical trials. to be most of and the large number of in which it is available for women and the of different of administration for men as trials et et al, et al, et al, et al, et al, et al, et al, have been published in which was to normal men to test the effects on sperm suppression at from to or were given in combination with or T or or for at 6 of the subjects treated with these hormonal combinations, achieved azoospermia and As with other progestins, a combination of or with et al, et al, et al, to be effective in terms of sperm suppression compared with given in combination with T et al, et al, et al, et al, et al, et al, 2002). of subjects received or or azoospermic compared with the of subjects that azoospermic after or of azoospermia after administration of in combination with testosterone testosterone enanthate or testosterone or T or rate of azoospermia achieved with each different mean of the azoospermic rates in the 2 of studies. ratio of azoospermia was T text and for papers have been published in which or were to subjects for In these studies, azoospermic and et al, et al, The combined administration of was more effective in sperm suppression of compared with the administration of or T of of azoospermia after enanthate or and testosterone injections or administration of and testosterone or rate of azoospermia achieved with each different mean of the azoospermic rates in the 2 of studies. ratio of azoospermia was T text and 6 for The progestins of this degrees of androgenic that with that of the exogenous The reported decrease of levels and of T from by these progestins may to T levels et al, 1995). these may explain the fact that the effects by most of the progestin when combined with androgens are to those reported with androgens, and a decrease in large-scale studies are to determine both and of in combination with or in the of progestins like or was to to the side effects observed with these progestins, the of the androgenic in the progestins was to provide in terms of and of sperm papers et al, et al, et al, et al, et al, et al, have been published in which the progestin at of or or as an of was combined with 100 or or with T subjects received 1 of these regimens for Azoospermia was achieved in of the subjects of and 100 of subjects whereas when the of was to azoospermia was achieved in of subjects of in combination with 100 or azoospermia in of and of of the In study et al, when administration was for weeks to allow for the suppression of gonadotropins and depletion of intratesticular T in sperm suppression was found compared with the same 100 from the of azoospermia was of of and time to azoospermia was weeks in the 2 groups, studies with and reported a decrease of that to be on the of both the progestin and the androgen and 100 These results suggest that some when combined with may be to induce the of azoospermia after administration of in combination with testosterone testosterone enanthate or T or T rate of azoospermia achieved with each different mean of the azoospermic rates in the 2 of studies. ratio of azoospermia was T text and for In this have published studies in which androgen-progestin hormonal combinations were to men for the purpose of sperm In the 40 years since the of in which male received an androgen-progestin combination have been published in the progestins were to men, it has that when alone progestins induce of androgen to gonadotropin suppression and possible direct effects on T that are to have a androgenic effect in women maintain androgen-dependent physiological in men if given androgens et al, Therefore, for the purpose of male contraception all progestins available be given in combination with androgens. The of profound gonadotropin suppression with the progestin alone would allow for the use of an androgen that is to maintain androgen-dependent physiological functions. However, available progestins have not been shown to induce such profound gonadotropin suppression when a if progestins are that are more in terms of gonadotropin suppression at that not This analysis of the data published in the literature these that when a progestin is in combination with an androgen, a profound suppression of spermatogenesis can be studies suggest that the suppressive of progestin are additive to range of degree of sperm suppression has been reported in the various studies with different and When optimal regimens were all progestins azoospermia or azoospermia in all men. Therefore, on the data published progestin seems to be to the in terms of spermatogenic the different regimens, the low effectiveness of the androgen-progestin combinations that included androgens was papers have reported on the combined administration of progestins with androgens suppression by these androgen-progestin regimens is compared with that achieved with regimens in which the 2 compounds have been given through injections or The levels in serum T levels or as in the case of T can explain this low These and levels may be to induce or maintain gonadotropin suppression, as has been suggested by the comparison of gonadotropin levels between 2 in which was given in combination with or (Meriggiola et al, 1997). few studies the of a hormonal to induce profound sperm suppression that can be eventually with In these preliminary trials, profound sperm suppression was with the high However, the to maintain suppression to et al, et al, recent studies in which different hormonal combinations have been used both in and in men have shown that it is possible to maintain sperm suppression for as as weeks with hormone than those used to induce the suppression et al, et al, et al, However, these recent have given results et al, The use of regimens for of sperm suppression may for the different to maintain and thus sperm suppression, with the 2 However, this concept and to be as the use of a hormonal for of sperm suppression may and decrease the as well as and decrease side effects of the contraceptive. of these trials has reported major effects that would of the hormonal However, only years of clinical use of the potential of hormone administration for contraception in men. It is that of T levels results in a of effects on When a progestin is added to the androgen for of sperm suppression, it be at that are than those used in Therefore, at these some of the progestin that are in contraceptives may physiological in male The of the progestin is also The use of progestins with and which in this case means progestins of androgenic or at the used for induction of suppression, the of these trials have shown that with the currently and are more effective in sperm suppression compared with the reported that the of men from different countries that contraceptives would be more compared with the currently available male contraceptives Therefore, these androgen-progestin combinations promise to be by many men as a to currently available recent reported that men of different the more to use compared with injections 1999). As with the of a range of of hormonal male contraceptives allow for and in men. Therefore, the of developing that can be or a high priority in the male contraceptive agenda. After many years since the of the hormonal results of the studies have demonstrated that male hormonal contraception can a recent has that the of men would be willing to use hormonal contraceptives and that women would their male to use or androgen-progestin provide optimal sperm suppression with minimal effects that promise to result in high of these III multicenter clinical trials are now for the contraceptive effectiveness of these hormonal more research is to with such as progestins with more gonadotropin activity, progestin or androgen or androgen to the of these regimens and